Generalized lymphadenopathy in the presence of acute Epstein–Barr virus infection as the initial manifestation of systemic lupus erythematous: A case report

Key Clinical Message Clinicians should carefully consider generalized lymphadenopathy, particularly post viral infections, as one of the possible systemic lupus erythematous (SLE) first signs regarding unusual joint involvements such as sacroiliitis. Late diagnosis of this autoimmune inflammatory disease, could lead to irreversible morbidity and higher mortality. Abstract Lymphadenopathy could represent various etiologies, including infections, malignancies, and rheumatologic diseases. SLE is known as the great mimicker which could be presented with different first manifestations. We report a 42‐year‐old woman in the acute phase of Epstein–Barr infection, admitted with polyarticular peripheral arthritis, sacroiliitis, and generalized lymphadenopathy. She had no similar history or taken unpasteurized dairy. Nodes were soft, mobile, and tender without skin change on top. During the process, she was diagnosed with SLE and discharged with prednisolone 30 mg/day and hydroxychloroquine 400 mg/day. After 2 weeks of follow‐up, all lymphadenopathy and symptoms were diminished. This case underscores the thousand faces innate of SLE. Clinical awareness would lead to an accurate diagnosis and early intervention.

lead to a chronic inflammatory state such as SLE disease. 3LE is a multifaceted and innovative disease that can have catastrophic impacts on any organ system.A typical SLE patient could present with multiple symptoms from any organ system.Fever, myalgias, fatigue, weight loss, arthralgia, and lupus nephritis are the most commonly presented manifestations.Less frequently, patients can also present with neuropsychiatric manifestations, myocardial infarctions, thromboembolic diseases and vasculitis.According to its wide variety of manifestations, SLE is known as the "great mimicker."There has been reports concerning atypical manifestations such as atypical chest pain and elevated troponin levels concerning for acute coronary syndrome, acute cutaneous LE, bullous LE, and enteritis and cystitis. 4,5erein we report 42-year-old women presented with generalized lymphadenopathy and fever in the presence of EBV infection, as initial manifestations of SLE followed by sacroiliitis for the first time.

| Case history/Examination
A 42-year-old woman was admitted to our hospital with myalgia, arthralgia, gait impairment, lower limb paresthesia, and pain in the left hip radiating to the anterior compartment of the thigh for 2 months.The pain would lessen with heat and exacerbated with activity.She also mentioned a 2 months history of night sweat but no weight loss.No history of aphthous or any similar mucocutaneous lesions was recorded, neither she had eating raw or unpasteurized dairy products.Her past medical history was remarkable for diabetes mellitus, ischemic heart disease, and hypothyroidism.The patient was afebrile with stable vital signs.In the physical examination, she had generalized lymphadenopathy involving inguinal, axillary, and cervical nodes on both sides with approximately 2 × 1 cm, 2 × 2 cm, and 1.5 × 2 cm, respectively.Nodes were soft, mobile, and painful with no skin changes on top.

| Outcome and follow-up
The patient fulfilled European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) 2019 criteria for SLE with 16 points (FANA = 1:100, inflammatory polyarthritis (6 points), as well as low C 3 and C 4 (4 points), and increased anti-ds DNA (6 points)). 6Intravenous administration of methylprednisolone (1000 mg/day) was started immediately and continued for 3 days.Finally, after 12 days she was discharged with prednisolone 30 mg/day (0.5 mg/kg/day) and hydroxychloroquine 400 mg/day.After 2 weeks of follow-up, all lymphadenopathy and symptoms were diminished.Regarding her poor compliance, she did not check for her follow-up sessions, hesitated taking medications and a year later, she was expired due to severe neuropsychiatric SLE with fever and cerebritis in another hospital.

| CASE DISCUSSION
Lymphadenopathy constitutes a vast majority of etiologies including infections (bacterial, brucellosis, tuberculosis; viral, HIV, EBV, herpes simplex virus, CMV, hepatitis B), cancer (lymphoma, leukemia), sarcoidosis, lupus erythematosus, amyloidosis, rheumatoid arthritis, and etc.To outline the cause of lymphadenopathy, a history, physical examination, and laboratory tests are obtained.
Although the exact gene-environment interactions remain vague, SLE includes multiple immunologic components such as hyperactivation of B cells, T cells, and monocytes resulting in the production of countless antibodies, autoantibodies, and cytokines. 5The clinical presentation and evolution of SLE consider an extensive variety.The 2019 EULAR/ACR released the most recent classification criteria for SLE. 6The criteria have two separate parts; clinical and immunological features.Clinical involvements consider constitutional, hematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, and renal system and immunological criteria include the presence of ANA, antiphospholipid antibodies, complement proteins and SLE-specific antibodies like anti-ds DNA, anti-Smith, and anti-histone DNA. 6To meet the criteria, the patient must represent at least one clinical criterion, positive ANA along with more than 10 points.
Lupus lymphadenopathy has been reported in 5%-7% in the newly diagnosed patients. 7It has been found that SLE patients first presented with lymphadenopathy more probably show constitutional symptoms such as fever, fatigue, and weight loss, hepatomegaly and splenomegaly, and additionally, decreased complements along with increased anti-dsDNA indicating that lymphadenopathy is a sign of disease activity. 6In the patient currently reported, the diagnosis of SLE was followed by ruling out lymphoma, infections and other causes of lymphadenopathy.Our patient met the criteria with 16 points, presenting with generalized lymphadenopathy as the first manifestation.
Interestingly, EBV VCA IgM results of the 42-year-old patient was positive representing an acute EBV infection.To date, there has been multiple studies approving the association of SLE flare and EBV infection similar to our patient. 8,9In a cross-sectional study of 40 patients with SLE, the EBV test reported positive in 67.5%, while half of patients had active disease. 10The viral load was significantly higher in patients with active disease independent of immunosuppressive medication.Another study also showed that SLE patients with positive EBV-VCA IgA had a higher prevalence of disease flare, confirming the association between EBV reactivation and SLE flare. 11EBV targets naïve B cells, by germinal center reaction, the infected cells enter the memory B cell group, consequently, the virus maintain the latency.Noncoding RNAs expressed by EBV, regulate B cell survival and induce the secretion of interferons by plasmacytoid dendritic cells, which cause unregulated T cell activation which could mimic SLE. 3 Moreover, Immunoglobin (Ig) A deficiency found in 6% of SLE patients could also counteract an epithelial EBV reactivation. 12Another mechanism contribute to molecular mimicry; Epstein-Barr virus nuclear antigen 1 (EBNA-1) has shown cross reactions with SLE-related autoantigens, resulting in the development of SLE. 13 Our patient had could be one of many SLE patients with positive EBV, presenting with disease activation by any of the mentioned mechanisms, however, this case is the first report of atypical presentation of SLE with positive acute serological EBV.We suggest further large-scale studies to evaluate the association of EBV and frequency of SLE activation, the clinical presentations, and prognosis.Furthermore, we suggest that positive EBV test could be possibly a sign for early diagnosis in patients with potential risk factors who do not complete SLE diagnosis criteria.This should be evaluated in long-term large-scale observations.Additionally, she had symptoms, signs, and an MRI report of mild sacroiliitis which is scarcely reported in SLE patients. 9Recently, a study represented higher titer of CRP as a potential risk factor of sacroiliac involvements in lupus patients. 14We suggest that other risk factors such as EBV reactivation, presence of different lupus specific antibodies should also be evaluated to predict possibility of sacroiliitis as well as rare first manifestations.

| CONCLUSION
Lymphadenopathy is considered one of rare onset manifestations.There have been previous case reports of lupus lymphadenopathy; however, the correlation between these nonfrequent presentations and viral reactivations remain vague.Future investigations should be performed to clarify possible risk factors of rare involvements of SLE in order to prevent a late diagnosis.More importantly, physicians should consider SLE as one of the prior differential diagnoses of lymphadenopathy for which a proper history, physical and laboratory examination, and lymph node biopsy is needed.
Initial laboratory tests of the patient results.
Specific immunologic tests of the patient.
T A B L E 2 antibody; HIV Ab, Human Immunodeficiency Virus antibody; LA antibody, lupus anticoagulant; RF, Rheumatoid Factor.